title: Ron tyrosine kinase receptor synergises with EGFR to confer adverse features in head and neck squamous cell carcinoma.
abstract: BACKGROUND
  Although EGFR inhibitors have shown some success in the treatment of head and neck squamous cell carcinomas (HNSCCs), the results are not dramatic. Additional molecular targets are urgently needed. We previously showed that the loss of Ron receptor activity significantly slowed squamous tumour growth and progression in a murine model. Based on these data, we hypothesised that Ron expression confers an aggressive phenotype in HNSCCs. We prospectively collected and evaluated 154 snap-frozen, primary HNSCCs for Ron and EGFR expression/phosphorylation. Biomarker correlation with clinical, pathological and outcome data was performed. The biological responses of HNSCC cell lines to Ron knockdown, its activation and the biochemical interaction between Ron and EGFR were examined.
  
  
  RESULTS
  We discovered that 64.3% (99 out of 154) HNSCCs expressed Ron. The carcinomas expressed exclusively mature functional Ron, whereas the adjacent nonmalignant epithelium expressed predominantly nonfunctional Ron precursor. There was no significant association between Ron and sex, tumour differentiation, perineural/vascular invasion or staging. However, patients with Ron+HNSCC were significantly older and more likely to have oropharyngeal tumours. Ron+HNSCC also had significantly higher EGFR expression and correlated strongly with phosphorylated EGFR (pEGFR). Newly diagnosed HNSCC with either Ron/pEGFR or both had lower disease-free survival than those without Ron and pEGFR. Knocking down Ron in SCC9 cells significantly blunted their migratory response to not only the Ron ligand, MSP, but also EGF. Stimulation of Ron in SCC9 cells significantly augmented the growth effect of EGF; the synergistic effect of both growth factors in SCC9 cells was dependent on Ron expression. Activated Ron also interacted with and transactivated EGFR.
  
  
  CONCLUSIONS
  Ron synergises with EGFR to confer certain adverse features in HNSCCs.
authors.affiliation: Department of Microbiology and Molecular Genetics, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: J
authors.initials: J
authors.lastname: Keller
authors.forename: A S
authors.initials: AS
authors.lastname: Nimnual
authors.forename: K R
authors.initials: KR
authors.lastname: Shroyer
authors.forename: C
authors.initials: C
authors.lastname: Joy
authors.forename: I
authors.initials: I
authors.lastname: Ischenko
authors.forename: C S
authors.initials: CS
authors.lastname: Chandler
authors.forename: L M
authors.initials: LM
authors.lastname: Dong
authors.forename: M J
authors.initials: MJ
authors.lastname: Hayman
authors.forename: E L
authors.initials: EL
authors.lastname: Chan
mesh_terms: D016475:3T3 Cells; D000368:Aged; D000818:Animals; D019556:COS Cells; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D016019:Survival Analysis
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases